The long term goal of this Project is to define the genetic and biological bases for abnormalities seen in individuals with Down syndrome (DS; Trisomy 21, Ts21), using genetically defined and genetically manipulated mouse model systems. The Down syndrome region of human Chromosome (Chr) 21 is conserved in at least three mouse chromosomes Chr 10, 16, and 17- with the largest segment in Chr 16. My research group has produced a mouse strain that carries segmental trisomy [Ts(1716)65Dn] for most of the region of mouse Chr 16 that is homologous with the Down syndrome region of human Chr 21 genes at dosage imbalance in this model by combining Ts65Dn with transgenes containing genes from the region of human Chr 21 that is conserved in mouse Chr 10; (2) study the effects of individual candidate genes in the Ts65DN segment by combining in mouse Chr 10; (2) study the effects of individual candidate genes in the Ts65Dn segment by combining it with targeted mutations for the single-minded (Sim2) and minibrain (Dyrk) homologs of Drosophila genes, which are important in central nervous system development and glycolysis; (3) analyze the behavior and pathology of the combining mice produced and (4) carry out neurological and electrophysiologic studies on the combination mice produced. The evaluation of neural function will include in vitro recording from fresh brain slices to assess synaptic transmission and plasticity. In vivo procedures, such as electrocorticograms and quantification of tremor activity also will be used. These assessments will be complemented by the analysis of hippocampal place cell activity and dendritic morphology of a limited number of strains. This research will provide not only a better understanding of the role of single genes in the Down syndrome phenotype but also a more complete adult mouse model for testing therapeutic intervention.